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J Mol Cell Cardiol. 2014 Dec;77:42-52. doi: 10.1016/j.yjmcc.2014.09.022. Epub 2014 Sep 28.

Sulforaphane prevents the development of cardiomyopathy in type 2 diabetic mice probably by reversing oxidative stress-induced inhibition of LKB1/AMPK pathway.

Author information

1
Department of Cardiology at the First Hospital of Jilin University, Changchun 130021, China; Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA.
2
Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA; The Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou 325035, China.
3
Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA.
4
Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY 40202, USA.
5
Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA; Department of Pathology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, China.
6
Department of Cardiology at the First Hospital of Jilin University, Changchun 130021, China. Electronic address: zhengyang@jlu.edu.cn.
7
Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA; The Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou 325035, China. Electronic address: l0cai001@louisville.edu.

Abstract

Type 2 diabetes mellitus (T2DM)-induced cardiomyopathy is associated with cardiac oxidative stress, inflammation, and remodeling. Sulforaphane (SFN), an isothiocyanate naturally presenting in widely consumed vegetables, particularly broccoli, plays an important role in cardiac protection from diabetes. We investigated the effect of SFN on T2DM-induced cardiac lipid accumulation and subsequent cardiomyopathy. Male C57BL/6J mice were fed a high-fat diet for 3months to induce insulin resistance, followed by a treatment with 100mg/kg body-weight streptozotocin to induce hyperglycemia; we referred to it as the T2DM mouse model. Other age-matched mice were fed a normal diet as control. T2DM and control mice were treated with or without 4-month SFN at 0.5mg/kg daily five days a week. At the study's end, cardiac function was assessed. SFN treatment significantly attenuated cardiac remodeling and dysfunction induced by T2DM. SFN treatment also significantly inhibited cardiac lipid accumulation, measured by Oil Red O staining, and improved cardiac inflammation oxidative stress and fibrosis, shown by down-regulating diabetes-induced PAI-1, TNF-α, CTGF, TGF-β, 3-NT, and 4-HNE expression. Elevated 4-HNE resulted in the increase of 4-HNE-LKB1 adducts that should inhibit LKB1 and subsequent AMPK activity. SFN upregulated the expression of Nrf2 and its downstream genes, NQO1 and HO-1, decreased 4-HNE-LKB1 adducts and then reversed diabetes-induced inhibition of LKB1/AMPK and its downstream targets, including sirtuin 1, PGC-1α, phosphorylated acetyl-CoA carboxylase, carnitine palmitoyl transferase-1, ULK1, and light chain-3 II. These results suggest that SFN treatment to T2DM mice may attenuate the cardiac oxidative stress-induced inhibition of LKB1/AMPK signaling pathway, thereby preventing T2DM-induced lipotoxicity and cardiomyopathy.

KEYWORDS:

Cardiac lipotoxicity; Cardiomyopathy; LKB1/AMPK pathway; Oxidative stress; Sulforaphane; Type 2 diabetes

PMID:
25268649
DOI:
10.1016/j.yjmcc.2014.09.022
[Indexed for MEDLINE]

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